pharmaceutical composition simultaneously having rapid-acting property and long-acting property

ABSTRACT

Disclosed is a pharmaceutical composition simultaneously having a rapid acting property and a long-acting property, comprising a sustained-release part coated with a water-insoluble polymer on the surface, comprising a first active pharmaceutical ingredient, at least one release control base selected from the group consisting of water-insoluble polymer, and water-soluble viscous polymer, and a pharmaceutically acceptable carrier; and, an immediate release part comprising a second active pharmaceutical ingredient and a pharmaceutically acceptable carrier. The pharmaceutical composition exhibits independent release properties of the immediate release part and the sustained-release part by coating the surface of the sustained-release part comprising an active pharmaceutical ingredient, a release control base and a pharmaceutically acceptable carrier with a water-insoluble polymer to separate it from the immediate release part, and it may be prepared by a relatively simple process without specification limitation to the contents and the kinds of usable pharmaceutically active ingredients.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of international application no.PCT/KR2010/006910 filed on Oct. 8, 2010, which claims all benefitsaccruing under 35 U.S.C. §119 from Korean Patent Application Nos.10-2009-0096315 filed on Oct. 9, 2009 and 10-2009-0104248 filed on Oct.30, 2009 earlier filed in the Korean Intellectual Property Office, theentire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This disclosure relates to a pharmaceutical composition simultaneouslyhaving a rapid-acting property and a long-acting property. Thepharmaceutical composition exhibits independent release properties of animmediate release part and a sustained-release part, and it may beprepared by a relatively simple process without limitation to thecomposition and the kinds of usable active pharmaceutical ingredients(API).

(b) Description of the Related Art

Currently, according to the progress of preparation technologies,developments of technologies for sustained-release of various drugs areunder progress in order to improve compliance of patients. Asustained-release preparation decreases the number of administrationwhile effectively inducing potential effects of drugs by maintainingpharmaceutical effects, compared to an immediate-release preparation,and it has a lot of advantages in terms of effectiveness and safety suchas reduction in side-effects or toxicity. However, for analgesics, etc.requiring immediate effects, a rapid acting property of rapidly reachingeffective blood concentration to exhibit analgesic effect, etc. afteradministration is also required. Thus, a development of preparationsimultaneously having a rapid-acting property and a long-acting propertyis required.

A representative preparation simultaneously having a rapid-actingproperty and a long-acting property includes Tylenol ER currentlymarketed by Janssen (U.S. Pat. No. 4,820,522), which simultaneouslycontains a determined drug dose containing a wicking agent and anerosion promoter in an immediate-release drug layer, and a powdercomposition and a determined drug dose containing an active matrixbinder (hydroxyethylcellulose) and a wicking agent (microcrystallinecellulose) in a sustained-release drug layer, and is a dual-layeredtablet prepared using a specific tableting machine.

As the existing technologies having the immediate-release part and thesustained-release part, a multi layer tablet prepared by depositing animmediate-release part and a sustained-release part, a core tabletprepared by forming a sustained-release part and then inserting it in animmediate-release part and dually tableting, an osmotic pump tablet, andspherical granules prepared by extrusion and spheronization have beenreported.

However, according to the existing technologies, specific equipments arerequired and the process is complicated. And, since in the existingtechnologies, both the immediate-release part and the sustained-releasepart are tableted in the form of a matrix or compression-molded,disintegration or release of the immediate-release part may be delayeddue to the base contained in the sustained-release part, and thus, itmay be difficult that the immediate-release part and thesustained-release independently exhibit release properties. Furthermore,they are difficult to be applied for a drug requiring high content.

SUMMARY OF THE INVENTION

Accordingly, the inventors studied on the pharmaceutical compositionthat may be prepared by a simple process, has no limitation to thecontents and the kinds of active active pharmaceutical ingredients, andmay exhibit independent release properties of the immediate release partand the sustained-release part, and completed the invention.

Therefore, it is an object of the present invention to provide apharmaceutical composition that may be prepared by a simple process, hasno limitation to the contents and the kinds of active pharmaceuticalingredients, and may exhibit independent release properties of theimmediate release part and the sustained-release part.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows dissolution rate of the pharmaceutical composition of thepresent invention with the composition of <Example 1-1> in water overtime.

FIG. 2 shows dissolution rates of Tramadol HCl and Acetaminophen of thepharmaceutical composition of the present invention with the compositionof <Example 1-2> at pH 1.2 and pH 6.8 over time.

FIG. 3 shows dissolution rate of the pharmaceutical composition of thepresent invention with the composition of <Example 2> in water overtime.

FIG. 4 shows dissolution rate of the pharmaceutical composition of thepresent invention with the composition of <Example 3> in water overtime.

FIG. 5 shows dissolution rate of the pharmaceutical composition of thepresent invention with the composition of <Example 4> in water overtime.

FIG. 6 shows dissolution rate of the pharmaceutical composition of thepresent invention with the composition of <Example 5> in water overtime.

FIG. 7 shows dissolution rate of the pharmaceutical composition of thepresent invention with the composition of <Example 6> in water accordingto time and the spray amount of the water-insoluble base.

FIG. 8 shows dissolution rate of the pharmaceutical composition of thepresent invention with the composition of <Example 7> in water overtime.

FIG. 9 shows dissolution rate of the pharmaceutical composition of thepresent invention with the composition of <Example 8> in water overtime.

FIG. 10 shows dissolution rates of the pharmaceutical compositions ofthe present invention with the compositions of <Example 9-1> and<Example 9-3> in water over time (Comparative Example: Tylenol ER).

FIG. 11 shows dissolution rate of the pharmaceutical composition of thepresent invention with the composition of <Example 10> in water overtime.

FIG. 12 shows dissolution rate of the pharmaceutical composition of thepresent invention with the composition of <Example 11> in water overtime.

FIG. 13 shows dissolution rate of the pharmaceutical composition of thepresent invention with the composition of <Example 12> in water overtime.

FIG. 14 shows dissolution rate of the pharmaceutical composition of thepresent invention with the composition of <Example 13> in water overtime.

FIG. 15 shows dissolution rate of the pharmaceutical composition of thepresent invention with the composition of <Example 14> in water overtime.

FIG. 16 shows dissolution rate of the pharmaceutical composition of thepresent invention with the composition of <Example 69> at pH 6.8 overtime.

DETAILED DESCRIPTION OF THE EMBODIMENTS

In order to achieve the above object, the present invention provide apharmaceutical composition comprising a sustained-release part coatedwith water-insoluble polymer on the surface, comprising a first activepharmaceutical ingredient, at least one release control base selectedfrom the group consisting of water-insoluble polymer, and water-solubleviscous polymer, and a pharmaceutically acceptable carrier; and, animmediate release part comprising a second active pharmaceuticalingredient and a pharmaceutically acceptable carrier.

Hereinafter, the present invention will be explained in detail.

The pharmaceutical composition of the present invention exhibitsindependent release properties of the immediate release part and thesustained-release part by coating the surface of the sustained-releasepart comprising an active pharmaceutical ingredient, a release controlbase and a pharmaceutically acceptable carrier with water-insolublepolymer to separate it from the immediate release part, it may beprepared by a relatively simple process without specification limitationto the contents and the kinds of usable active pharmaceuticalingredients, and it exhibits independent release properties of theimmediate release part and the sustained-release part without beingaffected by pH change.

The water-insoluble polymer may be those exhibiting a solubility of0.0001 g/ml of less in an aqueous solvent at any pH, and preferably oneor more selected from the group consisting of water-insoluble cellulose,water-insoluble cellulose derivatives, polymethacrylate,polyalkylacrylate, methacrylate-ethylacrylate based copolymer, and acombination thereof, but not limited thereto. The water-insolublecellulose may be preferably alkyl cellulose, more preferably ethylcellulose. The water-insoluble cellulose derivatives may be preferablyone or more selected from the group consisting of cellulose acetate,acetate phthalate, hydroxypropylmethylcellulose phthalate, and acombination thereof.

The water-soluble viscous polymer may exhibit a solubility of 0.01 g/mlor more in an aqueous solvent at any pH, and absorbs an aqueous solventin an aqueous solution of 10% w/v, 20° C. to exhibit viscosity change of1 mPas or more, based on the dry state. More preferably, it may be oneor more selected from the group consisting of hydroxylalkylcellulose,hydroxypropylalkylcellulose, polyalkyleneoxide, sodium alginate,povidone, natural or synthetic gums, polyvinylalcohol,carboxymethylcellulose sodium, and a combination thereof. Mostpreferably, it may be one or more selected fromhydroxypropylmethylcellulose, hydroxyethylcellulose, or a combinationthereof.

The pharmaceutical composition of the present invention comprises asustained-release part coated with water-insoluble polymer on thesurface and an immediate-release part.

In the pharmaceutical composition of the present invention, thesustained-release part and the immediate-release part are combined, andto exhibit independent release properties of the sustained-release partand the immediate-release part, the surface of the sustained-releasepart is coated with water-insoluble polymer to separate it from theimmediate-release part.

To exhibit independent release properties of the sustained-release partand the immediate-release part, the surface of the sustained-releasepart may be additionally coated with water-soluble viscous polymer, andmore preferably, it may be primarily coated with water-soluble viscouspolymer and secondarily coated with water-insoluble polymer.

In the examples, the surface of the sustained-release part is 1) coatedwith water-insoluble polymer (<Example 9-1> to <Example 68>), 2) coatedwith water soluble viscous polymer and additionally coated withwater-insoluble polymer (<Example 1-1> to <Example 8>), or 3) coatedwith water-insoluble polymer and then coated with water-soluble viscouspolymer, and additionally coated with water-insoluble polymer (<Example69>), and combined with an immediate-release part to prepare apharmaceutical composition of the present invention.

The sustained-release part comprises a first active pharmaceuticalingredient, at least one release control base selected from the groupconsisting of water-insoluble polymer and water-soluble viscous polymer,and pharmaceutically acceptable carrier, and the immediate-release partcomprises a second active pharmaceutical ingredient and apharmaceutically acceptable carrier.

Particularly, the first active pharmaceutical ingredient, the releasecontrol base, and the pharmaceutically acceptable carrier in thesustained-release part may be preferably mixed, but not limited thereto.

And, to control release of the sustained-release part, at least oneselected from the group consisting of water-insoluble polymer andwater-soluble viscous polymer may be used, and to more precisely controlthe release, a hydrophilic delivery vector or a hydrophobic deliveryvector may be additionally used.

The hydrophilic delivery vector may be selected from the groupconsisting of polyalkylene glycol, carboxyvinyl hydrophilic polymer, anda combination thereof, and more preferably, it may bepolyethyleneglycol, carbormer (Carbopol™), calcium carboxymethylcellulose, sodium carboxymethyl cellulose, etc. with a molecular weightof 400˜6,000, but not limited thereto.

The hydrophobic delivery vector may be selected from the groupconsisting of fatty acid, fatty acid ester, fatty alcohol, fatty acid(mono-, di-, tri-)glyceride, waxes, hydrogenated castor oil,hydrogenated vegetable oil, and a combination thereof. The fatty alcoholmay be cetostearyl alcohol, stearyl alcohol, lauryl alcohol, myristylalcohol, etc., the fatty acid ester may be glyceryl monostearate,glycerol monoleate, acetylated monoglyceride, tristearin, tripalmitin,cetyl ester wax, glyceryl palmitostearate, glyceryl behenate (Compritol888 ATO™), and the wax may be beeswax, carnauba wax, glycol wax, andcastor wax.

The sustained-release part and the immediate-release part may be in theform of independent granules, and the granules may be mixed in thepharmaceutical composition of the present invention, but not limitedthereto.

In the examples, the sustained-release composition comprising a activepharmaceutical ingredient, a release control based, and apharmaceutically acceptable carrier is prepared in the form of granulesusing a binding solution commonly used in the preparation of apharmaceutical composition, and the immediate-release compositioncomprising a active pharmaceutical ingredient and a pharmaceuticallyacceptable carrier is also prepared in the form of granules using abinding solution.

As explained, to prepare the pharmaceutical composition of the presentinvention, the sustained-release part and the immediate-release part arerespectively prepared and combined without requiring a specific process,and a separate process for tableting or compression molding in the formof a matrix is not required, and thus the process is very simple.

Furthermore, the contents and the kinds of the active pharmaceuticalingredients used in the pharmaceutical composition of the presentinvention are not limited. In the pharmaceutical composition, thesustained-release part and the immediate-release part are combined withbeing separated from each other, and the active pharmaceuticalingredient is contained respectively in the sustained-release part andthe immediate-release, and thus, the active pharmaceutical ingredientrequiring a rapid-acting property and the active pharmaceuticalingredient requiring a long-acting property may be independently usedwithout limitation.

And, when a active pharmaceutical ingredient is coated on aconventionally used core material, the amount of coating is limited,however, according to the pharmaceutical composition of the presentinvention, the content of the active pharmaceutical ingredient may beeasily controlled by controlling the contents of the activepharmaceutical ingredient when preparing the sustained-release part andthe immediate-release part, and the contents are not limited.

And, the release degree of the active pharmaceutical ingredientcontained in the sustained-release part may be controlled by controllingthe content of the release control base selected from the groupconsisting of water-insoluble polymer, water-soluble viscous polymer,and a combination thereof. And, the initial release amount and thesustained-release amount may be easily controlled by controlling themixing ratio of the sustained-release part and the immediate-releasepart.

In the pharmaceutical composition of the present invention, the firstactive pharmaceutical ingredient in the sustained-release part may be asingle or complex ingredient, and it may be one or more selected fromthe group consisting of acetaminophen, tramadol, Niacin, Pitavastatin,Rosuvastatin, Atorvastatin, Rebamipide, Metformin, Glimepiride,Pioglitazone, Sitagliptin, Voglibose, Levosulpiride, Mosapride,Trimebutine, Itopride, Cilostazol, Limaprost, Sarpogrelate, Nifedipine,Losartan, Valsartan, Telmisartan, Olmesartan, Candesartan, Benidipine,Carvedilol, Atenolol, Valaciclovir, Choline Alfoscerate,Acetyl-l-carnitine, Venlafaxine, Risperidone, Quetiapine, Gabapentin,Pregabalin, Levetiracetam, Rivastigmine, Aceclofenac, Eperisone,Bepotastine, Acyclovir, and a pharmaceutically acceptable salt thereof,but not limited thereto.

And, the second active pharmaceutical ingredient in theimmediate-release part may be a single or complex ingredient, and it maybe one or more selected from the group consisting of acetaminophen,tramadol, Niacin, Pitavastatin, Rosuvastatin, Atorvastatin, Rebamipide,Metformin, Glimepiride, Pioglitazone, Sitagliptin, Voglibose,Levosulpiride, Mosapride, Trimebutine, Itopride, Cilostazol, Limaprost,Sarpogrelate, Nifedipine, Losartan, Valsartan, Telmisartan, Olmesartan,Candesartan, Benidipine, Carvedilol, Atenolol, Valaciclovir, CholineAlfoscerate, Acetyl-l-carnitine, Venlafaxine, Risperidone, Quetiapine,Gabapentin, Pregabalin, Levetiracetam, Rivastigmine, Aceclofenac,Eperisone, Bepotastine, Acyclovir, and a pharmaceutically acceptablesalt thereof, but not limited thereto.

The active pharmaceutical ingredient in the sustained-release part andthe active pharmaceutical ingredient in the immediate-release part maybe the same or different, and they may be easily selected by a personhaving ordinary knowledge in the art.

And, the active ingredients may be preferably composed with thecomposition described in the following Table 1, according to the use orpurpose of the pharmaceutical composition, but not limited thereto.

TABLE 1 Complex ingredient (API) Single ingredient (API) A immediate-Immediate release + Sustained- release + A sustained-release + Asustained- release sustained- A sustained-release + B sustained-release + B (SR) release B immediate-release release sustained-releaseDigestiveduct ulcer rebamipide and diabetes metformin metforminglimepiride metformin voglibose metabolism metformin pioglitazonemetformin sitagliptin voglibose voglibose glimepiride pioglitazoneStomach levosulpiride function mosapride trimebutine itopride Blood andcilostazol hemopoietic limaprost organ sarpogrelate Cardiovascular CCB +ARB nifedipine nifedipine losartan system nifedipine valsartannifedipine telmisartan nifedipine olmesartan nifedipine candesartanbenidipine benidipine losartan benidipine valsartan benidipinetelmisartan benidipine olmesartan benidipine candesartan β- carvedilolcarvedilol losartan blocking carvedilol valsartan carvedilol telmisartancarvedilol olmesartan carvedilol candesartan atenolol atenolol losartanatenolol valsartan atenolol telmisartan atenolol olmesartan atenololcandesartan SLRA niacin niacin atorvastatin niacin rosuvastatin niacinpitavastatin (Antivirus) aciclovir Virals valaciclovir NervousNootropics choline system alfoscerate acetyl-1- carnitine SNRIvenlafaxine Antipsychotics risperidone quetiapine Analgesicsacetaminophen (Sustained- (Sustains- (Sustains-release + release +release + immediate-release) immediate- immediate- acetaminophenrelease) release) (Sustains-release) acetaminophen tramadol tramadolAnti gabapentin epileptics pregabalin levetiracetam Anti alzrivastigmine musculo- Anti- aceclofenac skeletal rheumatics systemMuscle eperisone relaxants Respiratory bepotastine system diabetes +hyperlipidemia metformin rosuvastatin

In the experimental examples of the present invention, acetaminophen ortramadol is used as a active pharmaceutical ingredient, the surface ofthe sustained-release part is coated with water-insoluble polymer orcoated with water-soluble viscous polymer and additionally coated withwater-insoluble polymer, and the release property of the preparedpharmaceutical composition is confirmed. As the result, it can be seenthat the sustained-release part and the immediate-release part exhibitindependent release properties (see acetaminophen in FIG. 1) withoutbeing affected by pH change (see FIG. 2), the release property may becontrolled by the contents of the sustained-release part and theimmediate-release part and the coating amount of the water-insolublepolymer (FIG. 7), the release property very similar to a representativeconventional preparation Tylenol ER simultaneously having a rapid-actingproperty and a long-acting property (FIG. 10) is shown, and the initialrelease property of the active pharmaceutical ingredient may be smoothlycontrolled by controlling the compositional ratio of thesustained-release part and the immediate-release part (FIG. 11 to FIG.12).

And, in the case of a pharmaceutical composition prepared by usingrosuvastatin, pitavastatin, atorvastatin calcium or niacin and coatingthe surface of the sustained-release part with water-insoluble polymer,the sustained-release part and the immediate-release part exhibitindependent release properties (FIG. 13 to FIG. 15).

And, in the case of a pharmaceutical composition prepared by usingvarious active ingredients described in the above Table 1 as well as therosuvastatin, pitavastatin, atorvastatin calcium or niacin, thesustained-release part and the immediate-release part exhibitindependent release properties, indicating that the kinds of the activepharmaceutical ingredient are not limited (Table 7 and Table 8, FIG.16).

The dosage form the pharmaceutical composition of the present inventionmay be preferably a tablet, but not limited thereto. The pharmaceuticalcomposition may be prepared in the form of a tablet by combining apharmaceutically acceptable carrier with the sustained-release part andthe immediate-release part and tableting, and the tablet may be preparedby a relatively simple process without requiring a special tabletingmachine.

The pharmaceutically acceptable carrier may be preferably selected fromexcipient, a disintegrating agent, a lubricant, or a combinationthereof, and the exipient, disintegrating agent, lubricant may be easilyselected by a person having ordinary knowledge in the art. Morepreferably, the excipient may include hydroxypropylcellulose,cellactose, kollidon, silicified microcrystalline cellulos, and acombination thereof, the disintegrating agent may include sodiumcroscarmellose, and the lubricant may include magnesium stearate.

According to the pharmaceutical composition of the present invention,the sustained-release part and the immediate-release part may exhibitindependent release properties by coating the surface of thesustained-release part comprising a active pharmaceutical ingredient, arelease control base and a pharmaceutically acceptable carrier withwater-insoluble polymer so as to separate it from the immediate-releasepart, the initial release property of the active pharmaceuticalingredient may be smoothly controlled by controlling the compositionalratio of the immediate-release part and the sustained-release part, andit may be prepared by a relatively simple process without limitation tothe contents and the kinds of usable active pharmaceutical ingredients.

Hereinafter, the present invention will be explained in detail by thefollowing Examples.

However, these examples are only to illustrate the present invention,and the scope of the present invention is not limited thereto.

EXAMPLE Preparation of a Pharmaceutical Composition SimultaneouslyHaving Rapid-Acting Property and Long-Acting Property 1) Preparation ofa Sustained-Release Part Having Long-Acting Property

According to <Example 1-1> to <Example 8> described in the followingTables 2 and 3, a binding solution was sprayed to a mixture of activepharmaceutical ingredients, a release control base and apharmaceutically acceptable carrier to prepare sustained-releasegranules, and a spray solution of water-soluble viscous polymer (5% w/w,mixing ethanol and water at 8:2) was sprayed to the prepared granules toprimarily coat them, and then, a spray solution of water-insolublepolymer (6% w/w, mixing ethanol and water at 9:1) was sprayed thereto tosecondarily coat them, thereby preparing a sustained-release part havinglong-acting property.

And, according to <Example 9-1> to <Example 68> described in thefollowing Table 3 to Table 5-2, a binding solution was sprayed to amixture of active pharmaceutical ingredients, a release control base anda pharmaceutically acceptable carrier to prepare sustained-releasegranules, and a spray solution of water-insoluble polymer (6% w/w,mixing ethanol and water at 9:1) was sprayed to the prepared granules tocoat them, thereby preparing a sustained-release part having long-actingproperty.

Additionally, according to <Example 69> described in the following Table6, a binding solution was sprayed to a mixture of active pharmaceuticalingredients, a release control base and a pharmaceutically acceptablecarrier to prepare sustained-release granules, and a spray solution ofwater-insoluble polymer (6% w/w, mixing ethanol and water at 9:1) wassprayed to the prepared granules to primarily coat them, and then, aspray solution of water-soluble viscous polymer (5% w/w, mixing ethanoland water at 8:2) was sprayed thereto to secondarily coat them, and aspray solution of water-insoluble polymer (6% w/w, mixing ethanol andwater at 9:1) to tertiary coat them, thereby preparing asustained-release part having long-acting property.

Specifically, acetaminophen and tramadol HCl were used as release drugsin <Example 1-1> to <Example 11> and <Example 69>, and the activeingredients of the sustained-release part described in Table 5-1 wereused as release drugs in <Example 15> to <Example 68>, and at least oneselected from colloidal silicon dioxide, methactylate-ethylacrylatebased copolymer (Registered trademark: Eudragit),hydroxypropylcellulose, hydroxyethylcellulose, calcium carbonate, sodiumlauryl sulfate, hydroxypropylmethylcellulose, microcrystallinecellulose, pregelatinized starch, polyethyleneoxide, croscarmellosesodium, and ethylcellulose were mixed therewith, and then, a bindingsolution was sprayed to prepare sustained-release granules.

Water-soluble viscous polymer was sprayed to the preparedsustained-release granules to primarily coat them, and water-insolublepolymer was sprayed to the primarily coated sustained-release granulesto secondarily coat them (<Example 1-1> to <Example 8>).

Alternatively, only water-insoluble polymer was sprayed to the preparedsustained-release granules to coat them (<Example 9-1> to <Example 11>,and <Example 15> to <Example 68>).

Alternatively, water-insoluble polymer was sprayed to the preparedsustained-release granules to primarily coat them, water-soluble viscouspolymer was sprayed to the primarily coated sustained-release granulesto secondarily coat them, and then, water-insoluble polymer wasadditionally sprayed to the secondarily coated sustained-releasegranules to tertiary coat them (<Example 69>).

As the water-soluble viscous polymer, at least one selected fromhydroxypropylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose, and polyethyleneoxide was used. As thewater-insoluble polymer, at least one selected from ethylcellulose,methacrylate-ethylacrylate based copolymer (Registered trademark:Eudragit), and microcrystalline cellulose was used.

Meanwhile, according to <Example 12> to <Example 14> described in thefollowing Table 4, a binding solution was sprayed to a sustained-releasemixture to prepare sustained-release granules, and water-insolublepolymer was sprayed to the prepared granules to coat them, therebypreparing a sustained-release part having long-acting property.

Specifically, in <Example 12> to <Example 14>, Niacin was used asrelease drug, and methacrylate-ethylacrylate based copolymer (Registeredtrademark: Eudragit) and hydroxyethylcellulose were mixed therewith, andthen, a binding solution was sprayed thereto to preparesustained-release granules, and then, water-insoluble polymerethylcellulose was sprayed to the sustained-release granules to coatthem.

2) Preparation of an Immediate-Release Part Having Rapid-Acting Property

According to <Example 1-1> to <Example 14> described in the followingTables 2 to 4, and <Example 15> to <Example 69> described in thefollowing Tables 5-1 to 6, a binding solution was sprayed to animmediate-release mixture to prepare immediate-release granules.

Specifically, acetaminophen was used as release drug in <Example 1-1> to<Example 9-3> and <Example 69> described in the following Tables 2, 3and 6, and acetaminophene and tramadol were used as release drugs in<Example 10> and <Example 11> described in Table 3, and at least oneselected from lactose, croscarmellose sodium, colloidal silicon dioxide,hydroxypropylcellulose, microcrystalline cellulose, pregelatinizedstarch, low-substituted hydroxypropylcellulose, and powdered cellulosewere mixed therewith, and then, a binding solution was sprayed theretoto prepare immediate-release granules.

Meanwhile, in <Example 12> to <Example 14> described in the followingTable 4 and <Example 15> to <Example 68> described in the followingTables 5-1 and 5-2, the active ingredients of the immediate-release partwere used as release drugs, and a binding solution was sprayed to theimmediate-release mixture to prepare immediate-release granules.

Specifically, in <Example 12> to <Example 14> and <Example 15> to<Example 68>, the active ingredients of the immediate-release partdescribed in Table 4 and Table 5-1 were used as release drugs, and atleast one selected from colloidal silicon dioxide, microcrystallinecellulose, hydroxypropylcellulose, calcium carbonate, magnesiumaluminometasilicate, and tribasic calcium phosphate were mixedtherewith, and then, a binding solution was sprayed to prepareimmediate-release granules.

3) Preparation of Pharmaceutical Composition Simultaneously HavingRapid-Acting Property and Long-Acting Property 3-1) Example 12 to 14, 17to 19, 22, 23, 32 to 36, 38 to 42, 44 to 48, 50 to 54, 68

The compositions were prepared substantially by the same method as theabove 1) and 2), except that a sustained-release part was prepared usingthe first active pharmaceutical ingredient and an immediate-release partwas prepared using the second active pharmaceutical ingredient of thecomplex active ingredients as described in Table 4, Table 5-1 and Table5-2, and excipient and a disintegrating agent were added to the preparedsustained-release part and the immediate-release part, and a lubricantwas additionally added thereto, and then, the mixture was tableted toprepare a tablet with a hardness of 12˜20 kp. Specifically,hydroxypropylcellulose was used as the excipient, croscarmellose sodiumwas used as the disintegrating agent, and magnesium stearate was used asthe lubricant.

3-2) Example 16, 21, 31, 37, 43, 49, 56, 57

The compositions were prepared substantially by the same method as theabove 1), except that only a sustained-release part was prepared using asingle active ingredient as described in the following Tables 5-1 and5-2, excipient and a disintegrating agent were added to the preparedsustained-release part and a lubricant was additionally added thereto,and then, the mixture was tableted to prepare a tablet with a hardnessof 12˜20 kp. Specifically, hydroxypropylcellulose was used as theexcipient, croscarmellose sodium was used as the disintegrating agent,and magnesium stearate was used as the lubricant.

3-3) Example 15, 24 to 30, 55, 58 to 67

The compositions were prepared substantially by the same method as theabove 1) and 2), except that a sustained-release part and animmediate-release part were prepared using a single active ingredient asdescribed in the following Tables 5-1 and 5-2, excipient and adisintegrating agent were added to the prepared sustained-release partand immediate-release part and a lubricant was additionally added, andthen, the mixture was tableted to prepared a table with a hardness of12˜20 kp. Specifically, hydroxypropylcellulose was used as theexcipient, croscarmellose sodium was used as the disintegrating agent,and magnesium stearate was used as the lubricant.

3-4) Example 20

The composition was prepared substantially by the same method as theabove 1), except that only a sustained-release part was prepared usingcomplex active ingredient as described in Tables 5-1 and 5-2, excipientand a disintegrating agent were added to the prepared sustained-releasepart and a lubricant was additionally added, and then, the mixture wastableted to prepared a table with a hardness of 12˜20 kp. Specifically,hydroxypropylcellulose was used as the excipient, croscarmellose sodiumwas used as the disintegrating agent, and magnesium stearate was used asthe lubricant.

3-5) Example 1-1 to 9-3, 69

The compositions were prepared substantially by the same method as theabove 1) and 2), except that only a sustained-release part was preparedusing a first active pharmaceutical ingredient (tramadol HCl) and asustained-release part and an immediate-release part were prepared usinga second active pharmaceutical ingredient (acetaminophen) as describedin Tables 2, 3 and 6, and excipient and a disintegrating agent wereadded to the prepared sustained-release part and a lubricant wasadditionally added, and then, the mixture was tableted to prepare atablet with hardness of 12˜20 kp. Specifically, hydroxypropylcellulosewas used as the excipient, croscarmellose sodium was used as thedisintegrating agent, and magnesium stearate was used as the lubricant.

3-6) Example 10 and 11

The compositions were prepared substantially by the same method as theabove 1) and 2), except that a sustained-release part and animmediate-release part were prepared using a first active pharmaceuticalingredient (tramadol HCl) and a sustained-release part and animmediate-release part were prepared using a second activepharmaceutical ingredient (acetaminophen), and excipient and adisintegrating agent were added to the prepared sustained-release partand a lubricant was additionally added, and then, the mixture wastableted to prepare a tablet with hardness of 12˜20 kp. Specifically,hydroxypropylcellulose was used as the excipient, croscarmellose sodiumwas used as the disintegrating agent, and magnesium stearate was used asthe lubricant.

TABLE 2 Compositions-I of the pharmaceutical compositions simultaneouslyhaving rapid-acting property and long-acting property Example ExampleExam- Exam- Exam- Ingredient 1-1 1-2 ple 2 Example 3 ple 4 ple 5 Example6 SUSTAINED GRANULES Mixture Acetaminophen 26.0%  24.4%   31.2% 28.9%  26.0%  31.2% 26.0%  RELEASE Tramadol HCl 5.0% 4.7%  6.0% 5.6%  5.0% 6.0% 5.0% PART Colloidal Silicon 0.05%  0.04%   0.04% 0.04%   0.07% 0.09% 0.05%  Dioxide Eudragit 3.3% 6.3%  4.7% 4.3%  3.3% 5.0%Hydroxyethylcellulose 3.3% 6.3%  3.3% Calcium carbonate 1.1% 1.1%  1.3%1.2% Sodium Lauryl 0.5% 0.4%  0.6% 0.6%  0.2% 0.2% SulfateHydroxypropylmethylcellulose 2.8% Microcrystalline  6.7% celluloseHydroxypropylcellulose  6.7% Binding Hydroxypropylcellulose 0.7% 0.6% 0.4% 0.4%  0.6%  0.5% 0.3% solution Water 2.5% 2.1%  1.4% 1.4%  2.1% 1.8% 1.1% Ethanol 2.5% 2.1%  1.4% 1.4%  2.1%  1.8% 1.1% FirstHydroxypropylmethylcellulose 0.3% 1.3%  0.5% 0.9% sprayHydroxyethylcellulose 2.5% 2.6%  2.5% 2.4%  0.5% Talc 1.0% 0.6%  0.4%0.5%  0.1% 0.3% Second Triethylcitrate 1.7% 1.2%  1.5% 1.2% 3.1% SprayPoylethyleneglycol 0.6% 1.2% 1.2% Triacetin  0.4%  0.3% Talc 1.7% 4.0% 1.5% 2.3%  0.8% 3.1% Eudragit  4.6%  4.5% Ethyl Cellulose 11.4%  13.2%  9.9% 11.7%   7.6%  7.5% primary: 6.15% secondary: 12.30% IMMEDIATEGRANULES Mixture Acetaminophen 17.3%  16.3%   20.8% 19.3%   17.3%  20.8%17.3%  RELEASE Tramadol HCl PART Lactose 3.7% 3.4%  4.3% 4.1%  3.7% 4.4% 3.7% Croscarmellose 0.7% 0.6%  0.8% 0.7%  0.7%  0.8% 0.7% sodiumColloidal Silicon 0.02%  0.02%   0.02% 0.02%   0.02%  0.02% 0.02% Dioxide Binding Hydroxypropylcellulose 0.6% 0.6%  0.8% 0.7%  0.7%  0.8%0.7% solution Water 2.1% 2.1%  2.8% 2.5%  2.5%  2.8% 2.5% Ethanol 2.1%2.1%  2.8% 2.5%  2.5%  2.8% 2.5% Additional Silicified 10.6%  5.7%  7.0%8.6%  10.6%  8.1% primary: Excipients Microcrystalline 18.35% cellulosesecondary: 12.20% Hydroxypropylcellulose 5.1% 2.5%  3.5% 3.4%  5.1% 5.0% 3.5% Croscarmellose 2.3% 2.4%  2.2% 2.3%  2.3%  2.2% 2.3% sodiumMagnesium Stearate 0.5% 0.5%  0.5% 0.5%  0.5%  0.5% 0.5% 100.0%  100.0% 100.0% 100.0%  100.0% 100.0% 100.0% 

TABLE 3 Compositions-II of the pharmaceutical compositionssimultaneously having rapid- acting property and long-acting propertyExample Exam- Example Exam- Ingredient Example 7 Example 8 Example 9-19-2 ple 9-3 10 ple 11 SUSTAINED GRANULES Mixture Acetaminophen 33.9% 32.5%  30.8%  30.8%   30.8% 20.8%   31.2% RELEASE Tramadol HCl 6.5% 6.2%2.4%  3.6% PART Colloidal 0.05%  0.05%  0.05%  0.05%   0.05% 0.05%  0.05% Silicon Dioxide Eudragit 3.6% 0.5% 5.4%  3.6% 5.7%  8.5% EthylCellulose 3.6% Hydroxyethylcellulose 3.6% 0.5% Microcrystalline 3.8%cellulose polyethyleneoxide 1.8%  1.8% 0.3%  0.5% Binding Pregelatinied1.9% solution starch Ethyl Cellulose 0.5% 0.1% 0.5% 0.6%  0.5% 0.5% 0.8% Water 1.8% 6.7% 0.4% 1.8% 2.1%  1.8% 1.8%  2.8% Ethanol 1.8% 6.7%0.4% 1.8% 2.1%  1.8% 1.8%  2.8% First Hydroxyethylcellulose 0.5% 0.5%spray Second Triacetin 0.8% 0.4% 0.4%  0.7% spray Eudragit 4.8% 4.6%Ethyl Cellulose 8.0% 7.6% 5.3% 5.5%  5.5% 4.4%  6.7% IMMEDIATE GRANULESMixture Acetaminophen 22.6%  21.7%  37.6%  37.6%   37.6% 31.2%   20.8%RELEASE Tramadol HCl 3.6%  2.4% PART Colloidal 0.05%  0.03%  0.03% 0.03%   0.03% 0.03%   0.03% Silicon Dioxide Low-substituted 4.5%Hydroxypropyl Cellulose Microcrystalline 2.5% 3.7% 3.7%  3.7% 9.6%  5.8%cellulose Binding Pregelatinied 3.9% 1.3% 1.9% 1.9%  1.9% 1.3%  1.3%solution starch Water 13.7%  4.6% 6.7% 6.7%  6.7% 4.6%  4.6% Ethanol13.7%  4.6% 6.7% 6.7%  6.7% 4.6%  4.6% Additional Silicified 7.2% 7.8% 7.8% 10.6%   9.3% Excipients Microcrystalline cellulose Kollidon 4.2%3.3%  3.4% 5.6%  4.8% Cellactose 4.3% 12.3%  Croscarmellose 1.9% 3.0%2.8% 2.8%  2.8% 3.0%  3.0% sodium Magnesium 0.5% 0.5% 0.5% 0.5%  0.5%0.5%  0.5% Stearate 100.0%  100.0%  100.0%  100.0% 100.0%  100.0%

TABLE 4 Compositions-III of the pharmaceutical compositionssimultaneously having rapid- acting property and long-acting propertyExample Example Example Ingredient 12 13 14 SUSTAINED GRANULES MixtureNiacin 33.3% 33.3% 33.3% RELEASE Eudragit 10.3% 10.3% 10.3% PARTHydroxyethylcellulose 2.8% 2.8% 2.8% Binding Hydroxypropylcellulose 1.0%1.0% 1.0% Solution water 2.8% 2.8% 2.8% ethanol 2.8% 2.8% 2.8% Firstspray Triethylcitrate 1.0% 1.0% 1.0% Talc 1.0% 1.0% 1.0% Ethyl Cellulose10.4% 10.4% 10.4% IMMEDIATE GRANULES mixture Rosuvastatin 0.3% RELEASEPitavastatin 0.1% PART Atorvastatin calcium 0.6% Niacin 22.2% 22.2%22.2% Tribasic Calcium Phosphate 1.4% Magnesium 1.4% AluminometasilicateCalcium carbonate 1.4% Colloidal Silicon Dioxide 0.1% 0.1% 0.1%Microcrystalline cellulose 3.3% 3.3% 3.3% Binding Hydroxypropylcellulose0.8% 0.8% 0.8% solution water 2.8% 2.8% 2.8% Ethanol 2.8% 2.8% 2.8%Additional Kollidon 4.0% 4.0% 4.0% Excipients SilicifiedMicrocrystalline 5.1% 5.3% 4.8% cellulose Croscarmellose sodium 2.5%2.5% 2.5% Magnesium Stearate 0.5% 0.5% 0.5% 100.0% 100.0% 100.0%

TABLE 5-1 Compositions-IV of the pharmaceutical compositionssimultaneously having rapid-acting property and long-acting propertySustained-release part Granules Mixture Binding solution ColloidalHydroxy Hydroxy Active Silicon ethyl Microcrystalline Croscarmellosepropyl Ingredient ingredient Dioxide Eudragit cellulose cellulose sodiumcellulose water ethanol Example Rebamipide 0.1%  3.6% 3.6% 3.6% 0.3%0.6% 10% solid cont. 15 17.8% Example Metformin 0.1% 5.30% 5.3% 5.3%0.7% 1.4% 10% solid cont. 16 HCl 53.0% Example Metformin 0.1% 5.26% 5.3%5.3% 0.7% 1.4% 10% solid cont. 17 HCl 53.1% Example Metformin 0.1% 5.02%5.0% 5.0% 0.7% 1.3% 10% solid cont. 18 HCl 53.0% Example Metformin 0.1%4.74% 4.7% 4.7% 0.6% 1.2% 10% solid cont. 19 HCl 53.0% Example Metformin0.1% 5.29% 5.29%  5.29%  0.69%  1.39%  10% solid cont. 20 HCl 52.9%Voglibose 0.05% Example Voglibose 1.88% 1.9% 5.6% 1.9% 0.2% 10% solidcont. 21 0.8% Example Voglibose 1.81% 1.8% 5.4% 1.8% 0.2% 10% solidcont. 22 0.8% Example Voglibose 1.41% 1.4% 4.2% 1.4% 0.2% 10% solidcont. 23 0.6% Example Levosulpiride 5.64% 5.6% 5.6% 0.5% 0.9% 10% solidcont. 24 28.2% Example Mosapride 4.85% 4.8% 4.8% 0.4% 0.8% 10% solidcont. 25 citrate 24.2% Example Trimebutine 6.58% 6.6% 6.6% 0.5% 1.1% 10%solid cont. 26 maleate 32.9% Example Itopride 6.57% 6.6% 6.6% 0.5% 1.1%10% solid cont. 27 HCl 32.9% Example Cilostazol 6.46% 6.5% 0.5% 0.9% 10%solid cont. 28 32.3% Example Limaprost 12.45%  12.5%  12.5%  0.4% 2.0%10% solid cont. 29 Alpha- Cyclodextrin Clathrate 0.6% ExampleSarpogrelate 0.1% 6.57% 6.6% 6.6% 0.5% 1.1% 10% solid cont. 30 HCl 32.9%Example Nifedipine 10.34%  6.9% 0.7% 1.4% 10% solid cont. 31 51.7%Immediate-release part Granules Mixture Binding solutioon AdditionalExcipients Colloidal Hydroxy Hydroxy Active Microcrystalline Siliconpropyl propyl Croscarmellose Magnesium Ingredient ingredient celluloseDioxide cellulose water ethanol cellulose sodium Stearate ExampleRebamipide 26.6% 0.1% 0.7% 10% solid cont. 4.2% 2.1% 0.6% 15 26.6%Example 3.6% 1.8% 0.5% 16 Example Glimepiride 3.6% 1.8% 0.5% 17 0.2%Example Pioglitazone 3.6% 1.8% 0.5% 18 HCl 1.7% Example Sitagliptin 4.7%0.0% 0.2% 10% solid cont. 3.7% 1.8% 0.5% 19 phosphate monohydrate 4.7%Example 3.6% 1.8% 0.5% 20 Example 76.3% 4.4% 2.2% 0.7% 21 ExampleGlimepiride 73.3% 4.4% 2.2% 0.7% 22 3.6% Example Pioglitazone 57.1% 4.5%2.2% 0.7% 23 HCl 23.2% Example Levosulpiride 16.9% 0.3% 0.6% 10% solidcont. 3.9% 2.0% 0.6% 24 14.1% Example Mosapride 32.3% 4.0% 2.0% 0.6% 25citrate 8.1% Example Trimebutine 4.9% 0.1% 0.4% 10% solid cont. 3.8%1.9% 0.6% 26 maleate 16.4% Example Itopride 4.9% 0.2% 0.4% 10% solidcont. 3.8% 1.9% 0.6% 27 HCl 16.4% Example Cilostazol 7.2% 0.1% 0.6% 10%solid cont. 3.9% 2.0% 0.6% 28 23.9% Example Limaprost 30.8% 9.3% 4.7%1.4% 29 Alpha- Cyclodextrin Clathrate 0.3% Example Sarpogrelate 4.9%0.1% 0.4% 10% solid cont. 3.8% 1.9% 0.6% 30 HCl 16.4% Example 3.6% 1.8%0.5% 31 Sustained-release part Granules Mixture Binding solutionColloidal Hydroxy Hydroxy Active Silicon ethyl MicrocrystallineCroscarmellose propyl Ingredient ingredient Dioxide Eudragit cellulosecellulose sodium cellulose water ethanol Example Nifedipine 4.60% 3.1%0.3% 0.6% 10% solid cont. 32 23.0% Example Nifedipine 3.46% 2.3% 0.2%0.5% 10% solid cont. 33 17.3% Example Nifedipine 5.17% 3.4% 0.3% 0.7%10% solid cont. 34 25.9% Example Nifedipine 5.27% 3.5% 0.4% 0.7% 10%solid cont. 35 26.4% Example Nifedipine 4.16% 2.8% 0.3% 0.6% 10% solidcont. 36 20.8% Example Benidipine 8.62% 8.6% 8.6% 0.7% 1.4% 10% solidcont. 37 HCl 43.1% Example Benidipine 0.98% 1.0% 1.0% 0.1% 0.2% 10%solid cont. 38 HCl 4.9% Example Benidipine 0.64% 0.6% 0.6% 0.1% 0.1% 10%solid cont. 39 HCl 3.2% Example Benidipine 1.19% 1.2% 1.2% 0.1% 0.2% 10%solid cont. 40 HCl 5.9% Example Benidipine 1.23% 1.2% 1.2% 0.1% 0.2% 10%solid cont. 41 HCl 6.2% Example Benidipine 0.84% 0.8% 0.8% 0.1% 0.1% 10%solid cont. 42 HCl 4.2% Example Carvedilol 7.26% 9.1% 7.3% 0.7% 1.4% 10%solid cont. 43 45.4% Example Carvedilol 4.45% 4.5% 4.5% 0.4% 0.8% 10%solid cont. 44 27.8% Example Carvedilol 3.59% 3.6% 3.6% 0.3% 0.7% 10%solid cont. 45 22.5% Example Carvedilol 4.84% 4.8% 4.8% 0.4% 0.9% 10%solid cont. 46 30.3% Example Carvedilol 4.91% 4.9% 4.9% 0.5% 0.9% 10%solid cont. 47 30.7% Example Carvedilol 4.14% 4.1% 4.1% 0.4% 0.8% 10%solid cont. 48 25.9% Example Atenolol 8.62% 8.6% 8.6% 0.7% 1.4% 10%solid cont. 49 43.1% Example Atenolol 6.57% 6.6% 6.6% 0.5% 1.1% 10%solid cont. 50 32.9% Immediate-release part Granules Mixture Bindingsolution Additional Excipients Colloidal Hydroxy Hydroxy ActiveMicrocrystalline Silicon propyl propyl Croscarmellose MagnesiumIngredient ingredient cellulose Dioxide cellulose water ethanolcellulose sodium Stearate Example 32 Losartan 11.5% 0.4% 1.0% 10% solidcont. 4.1% 2.1% 0.6% Potassium 38.4% Example 33 Valsartan 13.8% 0.3%1.2% 10% solid cont. 4.3% 2.1% 0.6% 46.1% Example 34 Telmisartan 10.3%0.4% 0.9% 10% solid cont. 4.1% 2.0% 0.6% 34.5% Example 35 Olmesartan35.2% 0.4% 0.9% 10% solid cont. 4.1% 2.0% 0.6% medoxomil 8.8% Example 36Candesartan 41.6% 0.3% 2.1% 10% solid cont. 4.2% 2.1% 0.6% cilexetil11.1% Example 37 3.6% 1.8% 0.5% Example 38 Losartan 18.4% 0.6% 1.6% 10%solid cont. 4.5% 2.2% 0.7% Potassium 61.3% Example 39 Valsartan 19.3%0.4% 1.7% 10% solid cont. 4.5% 2.3% 0.7% 64.2% Example 40 Telmisartan17.8% 0.7% 1.5% 10% solid cont. 4.5% 2.2% 0.7% 59.5% Example 41Olmesartan 61.5% 0.8% 1.5% 10% solid cont. 4.5% 2.2% 0.7% medoxomil15.4% Example 42 Candesartan 62.9% 0.5% 3.1% 10% solid cont. 4.5% 2.3%0.7% cilexetil 16.8% Example 43 3.6% 1.8% 0.5% Example 44 Losartan  8.4%0.3% 0.7% 10% solid cont. 4.0% 2.0% 0.6% Potassium 27.8% Example 45Valsartan 10.8% 0.2% 0.9% 10% solid cont. 4.1% 2.1% 0.6% 35.9% Example46 Telmisartan  7.3% 0.3% 0.6% 10% solid cont. 3.9% 2.0% 0.6% 24.2%Example 47 Olmesartan 24.5% 0.3% 0.6% 10% solid cont. 3.9% 2.0% 0.6%medoxomil 6.1% Example 48 Candesartan 31.0% 0.3% 1.6% 10% solid cont.4.0% 2.0% 0.6% cilexetil 8.3% Example 49 3.6% 1.8% 0.5% Example 50Losartan  4.9% 0.2% 0.4% 10% solid cont. 3.8% 1.9% 0.6% Potassium 16.4%Sustained-release part Granules Mixture Binding solution ColloidalHydroxy Hydroxy Active Silicon ethyl Microcrystalline Croscarmellosepropyl Ingredient ingredient Dioxide Eudragit cellulose cellulose sodiumcellulose water Ethanol Example 51 Atenolol 5.76% 5.8% 5.8% 0.5% 0.9%10% solid cont. 28.8% Example 52 Atenolol 6.90% 6.9% 6.9% 0.6% 1.1% 10%solid cont. 34.5% Example 53 Atenolol 6.95% 7.0% 7.0% 0.6% 1.1% 10%solid cont. 34.8% Example 54 Atenolol 6.29% 6.3% 6.3% 0.5% 1.0% 10%solid cont. 31.4% Example 55 Valaciclovir 0.0% 6.35% 6.3% 6.3% 0.5% 1.0%10% solid cont. HCl 31.7% Example 56 Choline 0.1% 8.23% 8.2% 8.2% 0.7%1.3% 10% solid cont. Alfoscerate 41.2% Example 57 Acetyl-l- 0.1% 8.23%8.2% 8.2% 0.7% 1.3% 10% solid cont. carnitine HCl 41.2% Example 58Venlafaxine 6.09% 6.1% 6.1% 0.4% 0.9% 10% solid cont. HCl 24.4% Example59 Risperidone 1.36% 1.4% 0.1% 0.2% 10% solid cont. 6.8% Example 60Quetiapine 4.21% 4.2% 4.2% 0.4% 0.8% 10% solid cont. fumarate 28.0%Example 61 Gabapentin 0.1% 3.83% 3.8% 3.8% 0.5% 1.0% 10% solid cont.38.3% Example 62 Pregabalin 3.87% 7.8% 3.9% 0.4% 0.8% 10% solid cont.25.8% Example 63 Levetiracetam 0.1% 5.16% 5.2% 5.2% 0.4% 0.8% 10% solidcont. 25.8% Example 64 Rivastigmine 0.69% 1.4% 1.4% 0.1% 0.2% 10% solidcont. 6.9% Example 65 Aceclofenac 5.31% 5.3% 5.3% 0.4% 0.9% 10% solidcont. 26.5% Example 66 Eperisone 8.62% 8.6% 8.6% 0.5% 1.1% 10% solidcont. HCl 28.7% Example 67 Bepotastine 6.20% 6.2% 6.2% 0.4% 0.9% 10%solid cont. besilate 24.8% Example 68 Metformin 0.1% 5.24% 5.2% 5.2%0.7% 1.4% 10% solid cont. HCl 52.4% Immediate-release part GranulesMixture Binding solution Additional Excipients Colloidal Hydroxy HydroxyActive Microcrystalline Silicon propyl propyl Croscarmellose MagnesiumIngredient ingredient cellulose Dioxide cellulose water Ethanolcellulose sodium Stearate Example Valsartan 6.9% 0.1% 0.6% 10% solidcont. 3.9% 2.0% 0.6% 51 23.0% Example Telmisartan 4.1% 0.2% 0.4% 10%solid cont. 3.8% 1.9% 0.6% 52 13.8% Example Olmesartan 13.9% 0.2% 0.3%10% solid cont. 3.8% 1.9% 0.6% 53 medoxomil 3.5% Example Candesartan18.9% 0.2% 0.9% 10% solid cont. 3.8% 1.9% 0.6% 54 cilexetil 5.0% ExampleValaciclovir 4.8% 0.0% 0.5% 10% solid cont. 3.7% 1.8% 0.6% 55 HCl 15.9%Example 3.4% 1.7% 0.5% 56 Example 3.4% 1.7% 0.5% 57 Example Venlafaxine7.3% 0.2% 0.8% 10% solid cont. 3.8% 1.9% 0.6% 58 HCl 24.4% ExampleRisperidone 68.1% 3.4% 1.9% 10% solid cont. 4.5% 2.3% 0.7% 59 6.8%Example Quetiapine 8.4% 0.6% 0.9% 10% solid cont. 4.0% 2.0% 0.6% 60fumarate 28.0% Example Gabapentin 5.7% 0.0% 0.6% 10% solid cont. 3.8%1.9% 0.6% 61 19.2% Example Pregabalin 7.7% 0.2% 0.8% 10% solid cont.3.9% 1.9% 0.6% 62 25.8% Example Levetiracetam 7.7% 0.1% 0.8% 10% solidcont. 3.9% 1.9% 0.6% 63 25.8% Example Rivastigmine 68.7% 1.1% 1.9% 10%solid cont. 4.5% 2.2% 0.7% 64 6.9% Example Aceclofenac 8.0% 0.1% 0.9%10% solid cont. 4.0% 2.0% 0.6% 65 26.5% Example Eperisone 4.3% 0.1% 0.5%10% solid cont. 3.8% 1.9% 0.6% 66 HCl 14.4% Example Bepotastine 7.4%1.2% 0.8% 10% solid cont. 3.9% 2.0% 0.6% 67 besilate 24.8% ExampleRosuvastatin 0.3% 0.1% 0.0% 10% solid cont. 3.6% 1.8% 0.5% 68 calcium0.5%

TABLE 5-2 Compositions-IV of the pharmaceutical compositionssimultaneously having rapid-acting property and long-acting propertySustained- First spray release Ethyl ethanol water part spray CelluloseTriacetin Poylethyleneglycol 85% 15% Example 7.4% 1.1% 1.1% 6% solidcont. 15 Example 17.8% 2.7% 2.7% 6% solid cont. 16 Example 17.6% 2.6%2.6% 6% solid cont. 17 Example 16.8% 2.5% 2.5% 6% solid cont. 18 Example15.9% 2.4% 2.4% 6% solid cont. 19 Example 17.8% 2.7% 2.7% 6% solid cont.20 Example 3.1% 0.5% 0.5% 6% solid cont. 21 Example 3.0% 0.4% 0.4% 6%solid cont. 22 Example 2.3% 0.3% 0.3% 6% solid cont. 23 Example 11.6%1.7% 1.7% 6% solid cont. 24 Example 10.0% 1.5% 1.5% 6% solid cont. 25Example 13.6% 2.0% 2.0% 6% solid cont. 26 Example 13.5% 2.0% 2.0% 6%solid cont. 27 Example 11.6% 1.7% 1.7% 6% solid cont. 28 Example 10.1%1.5% 1.5% 6% solid cont. 29 Example 13.6% 2.0% 2.0% 6% solid cont. 30Example 17.8% 2.7% 2.7% 6% solid cont. 31 Example 7.9% 1.2% 1.2% 6%solid cont. 32 Example 5.9% 0.9% 0.9% 6% solid cont. 33 Example 8.9%1.3% 1.3% 6% solid cont. 34 Example 9.1% 1.4% 1.4% 6% solid cont. 35Example 7.2% 1.1% 1.1% 6% solid cont. 36 Example 17.8% 2.7% 2.7% 6%solid cont. 37 Example 2.0% 0.3% 0.3% 6% solid cont. 38 Example 1.3%0.2% 0.2% 6% solid cont. 39 Example 2.5% 0.4% 0.4% 6% solid cont. 40Example 2.5% 0.4% 0.4% 6% solid cont. 41 Example 1.7% 0.3% 0.3% 6% solidcont. 42 Example 17.8% 2.7% 2.7% 6% solid cont. 43 Example 10.6% 1.6%1.6% 6% solid cont. 44 Example 8.6% 1.3% 1.3% 6% solid cont. 45 Example11.5% 1.7% 1.7% 6% solid cont. 46 Example 11.7% 1.8% 1.8% 6% solid cont.47 Example 9.9% 1.5% 1.5% 6% solid cont. 48 Example 17.8% 2.7% 2.7% 6%solid cont. 49 Example 13.5% 2.0% 2.0% 6% solid cont. 50 Example 11.9%1.8% 1.8% 6% solid cont. 51 Example 14.2% 2.1% 2.1% 6% solid cont. 52Example 14.3% 2.1% 2.1% 6% solid cont. 53 Example 13.0% 1.9% 1.9% 6%solid cont. 54 Example 15.7% 2.4% 2.4% 6% solid cont. 55 Example 20.4%3.1% 3.1% 6% solid cont. 56 Example 20.4% 3.1% 3.1% 6% solid cont. 57Example 13.2% 2.0% 2.0% 6% solid cont. 58 Example 2.0% 0.3% 0.3% 6%solid cont. 59 Example 10.5% 1.6% 1.6% 6% solid cont. 60 Example 12.8%1.9% 1.9% 6% solid cont. 61 Example 12.8% 1.9% 1.9% 6% solid cont. 62Example 12.8% 1.9% 1.9% 6% solid cont. 63 Example 2.7% 0.4% 0.4% 6%solid cont. 64 Example 10.9% 1.6% 1.6% 6% solid cont. 65 Example 14.1%2.1% 2.1% 6% solid cont. 66 Example 11.2% 1.7% 1.7% 6% solid cont. 67Example 17.6% 2.6% 2.6% 6% solid cont. 68

TABLE 6 Compositions-V of the pharmaceutical compositions simultaneouslyhaving rapid- acting property and long-acting property Example 69Ingredient Sustained- granules Mixture Acetaminophen 10.9%  release{circle around (1)} Tramadol HCl 6.3% part {circle around (1)} ColloidalSilicon Dioxide 0.04%  Eudragit 2.3% Hydroxyethylcellulose 2.3%Microcrystalline cellulose 2.3% Croscarmellose sodium 0.3% BindingHydroxypropylcellulose 0.2% solution Sodium Lauryl Sulfate 0.3% Water(30%) 12.4% solid cont. Ethanol (70%) First spray Ethyl Cellulose 2.5%NaOH 0.04%  Triacetin 0.4% Poylethyleneglycol 0.3% Water (10%) 6% solidcont. Ethanol (90%) Second spray Hydroxyethylcellulose 1.3%Hydroxypropylmethylcellulose 0.2% Water (15%) 6% solid cont. Ethanol(85%) Third spray Ethyl Cellulose 4.7% Triacetin 0.7% Poylethyleneglycol0.7% Water (10%) 6% solid cont. Ethanol (90%) Sustained- granulesMixture Acetaminophen 24.6%  release {circle around (2)} ColloidalSilicon Dioxide 0.1% part {circle around (2)} Eudragit 3.40%  BindingEthyl Cellulose 0.2% solution Water (30%) 9% solid cont. Ethanol (70%)Forth Ethyl Cellulose 4.7 spray Triacetin 0.7 Poylethyleneglycol 0.7Water (10%) 6% solid cont. Ethanol (90%) Immediate- Granules MixtureAcetaminophen 19.0%  release part Colloidal Silicon 0.1% DioxidePowdered Cellulose 5.90%  Croscarmellose 2.5% sodium BindingPolyvinylpyrrolidone 1.3% solution Water (100%) 7.1% solid cont.Additional Croscarmellose 0.4% Excipients sodium Magnesium Stearate 0.4%

EXPERIMENTAL EXAMPLES Dissolutoin Test of the Pharmaceutical Compositionof the Present Invention

1) Experimental Method

For the tablets prepared in the above Examples, dissolution test wasperformed. Specifically, the dissolution test was performed for 6 hoursunder conditions of 50 rotations/min using pH 1.2, pH 6.8 or water as adissolution medium according to a dissolution test second method ofgeneral test method of Korean Pharmacopoeia (Korean Food and DrugAdministration, 9^(th) edition, p1172). The dissolution solution wastaken each 5 ml at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 480 and600 minutes after initiation of the dissolution test and filtered, thefiltrate was used as a test solution and analyzed by HPLC, and theresults are shown in FIGS. 1 to 15, At this time, Tylenol ER tablet(Janssen Korea Ltd.: containing acetaminophen 650 mg, dual-layeredtablet) which is a representative drug simultaneously having arapid-acting property and a long-acting property was used as ComparativeExample.

2) Experimental Results

As shown in FIGS. 1 to 16, it can be seen that the pharmaceuticalcomposition of the present invention simultaneously has a rapid-actingproperty and a long-acting property because the sustained-release partand the immediate-release part are independently controlled, and it isnot sensitive to pH change and it may be used without limitation to thekinds of drugs.

Specifically, FIG. 1 shows the results of dissolution test of thecomposition of <Example 1-1> in water over time, and it is confirmedthat acetaminophen contained in the sustained-release part and theimmediate-release part is linearly sustained-released and immediatelyreleased, and Tramadol HCl contained only in the sustained-release partis sustained-released.

FIG. 2 shows the results of dissolution test of the composition of<Example 1-2> at pH 1.2 and pH 6.8 over time, and it is confirmed thatin the composition having different compositions ofhydroxyethylcellulose and Eudragit from the sustained-release granulesof <Example 1-1>, Tramadol HCl contained only in the sustained-releasepart and acetaminophen contained in the sustained-release part and theimmediate-release part are sustained-released and immediately releasedwithout being affected by pH change.

FIG. 3 shows the results of dissolution test of the composition of<Example 2> in water over time, and it is confirmed that in case thesustained-release part is granulated only with water-insoluble polymer,acetaminophen contained in the sustained-release part and theimmediate-release part is sustained-released and immediately released,and Tramadol HCl contained only in the sustained-release part isreleased with high initial dissolution rate.

FIG. 4 shows the results of dissolution test of the composition of<Example 3> in water over time, and it is confirmed that in casehydrophilic delivery vector polyethyleneglycol is added to thesustained-release second spray solution compared to <Example 2>,acetaminophen contained in the sustained-release part and theimmediate-release part is sustained-released and immediately released,and Tramadol HCl contained only in the sustained-release part issustained-released.

FIG. 5 shows the results of dissolution results of the composition of<Example 4> in water over time, and it is confirmed that in case thesustained-release part is granulated with microcrystalline cellulose andhydroxypropylcellulose, acetaminophen contained in the sustained-releasepart and the immediate-release part is sustained-released andimmediately released, and Tramadol HCl contained only in thesustained-release part is sustained-released.

FIG. 6 shows the results of dissolution test of the composition of<Example 5> in water over time, and it is confirmed that in case talc isexcluded from the spray solution coated on the sustained-releasegranules, acetaminophen contained in the sustained-release part and theimmediate-release part is sustained-released and immediately released,and Tramadol HCl contained only in the sustained-release part issustained-released.

FIG. 7 shows the results of dissolution test of the composition of<Example 6> in water over time, and it is confirmed that acetaminophencontained in the sustained-release part and the immediate-release partis sustained-released and immediately released, and Tramadol HClcontained only in the sustained-release part is sustained-released.Particularly, it is confirmed that the sustained-release andimmediate-release amounts of acetaminophen and Tramadol HCl may becontrolled by controlling the amount of water-insoluble polymerethylcellulose coated on the sustained-release part.

FIG. 8 shows the results of dissolution test of the composition of<Example 7> in water over time, and it is confirmed that in case sodiumlauryl sulfate and calcium carbonate are excluded from thesustained-release granules, acetaminophen contained in thesustained-release part and the immediate-release part issustained-released and immediately released, and Tramadol HCl containedonly in the sustained-release part is sustained-released.

FIG. 9 shows the results of dissolution test of the composition of<Example 8> in water over time, and it is confirmed that in caseacetaminophen and Tramadol HCl are separately granulated in thesustained-release part, acetaminophen contained in the sustained-releasepart and the immediate-release part is sustained-released andimmediately released, and Tramadol HCl contained only in thesustained-release part is sustained-released.

FIG. 10 shows the results of dissolution test of the compositions of<Example 9-1> to <Example 9-3> in water over time, and it is confirmedthat in case the kind of a base is changed in the mixture constitutingthe sustained-release granules, acetaminophen contained in thesustained-release part and the immediate-release part exhibits verysimilar release pattern to Tylenol ER.

FIG. 11 and FIG. 12 show the results of dissolution test of thecompositions of <Example 10> and <Example 11> in water over time, and itis confirmed that in case the immediate-release part and thesustained-release part are composed at a ratio of 3:2 <Example 10> andat a ratio of 2:3 <Example 11>, acetaminophen contained in thesustained-release part and the immediate-release part issustained-released and immediately released, and Tramadol HCl containedonly in the sustained-release part is sustained-released.

FIG. 13 shows the results of dissolution test of the composition of<Example 12> in water over time, and it is confirmed that Niacincontained in the sustained-release part and the immediate-release partis sustained-released and immediately released, and rosuvastatincontained only in the immediate-release part is immediately released.

FIG. 14 shows the results of dissolution test of the composition of<Example 13> in water over time, and it is confirmed that Niacincontained in the sustained-release part and the immediate-release partis sustained-released and immediately released, and pitavastatincontained only in the immediate-release part is immediately released.

FIG. 15 shows the results of dissolution test of the composition of<Example 14> in water over time, and it is confirmed that Niacincontained in the sustained-release part and the immediate-release partis sustained-released and immediately released, and atrovastatincontained only in the immediate-release part is immediately released.

FIG. 16 shows the results of dissolution test of the composition of<Example 69> at pH 6.8 over time, and the following Table 7 and Table 8show the results of dissolution test of the compositions of <Example 15>to <Example 40> and <Example 41> to <Example 69> at pH 6.8 over time,and it is confirmed that the active ingredients contained in thesustained-release part are sustained-released and the active ingredientscontained only in the immediate-release part are immediately released.

As explained, according to the pharmaceutical composition of the presentinvention, problems of delay in disintegration or delay in release ofthe active ingredients of the immediate-release part due to theinfluence of the sustained-release part may not be caused, thesustained-release part and the immediate-release part may exhibitindependent release properties, and the contents or kinds of the activeingredients requiring immediate-release or sustained-release are notlimited because the active ingredients are contained respectively in thesustained-release part and the immediate-release part and independentlyreleased, and stable dissolution property may be obtained even at pHchange, and thus, improved therapeutic effect may be anticipated.

TABLE 7 Dissolution rate at pH 6.8 under conditions of second method 50rpm over time (%) Example Ingredients 0 min 30 min 60 min 180 min 360min 600 min 15 Rebamipide 0.0% 59.7% 65.2% 75.3% 90.0% 99.0% 16Metformin HCl 0.0% 25.1% 39.4% 70.9% 88.8% 97.2% 17 Glimepiride 0.0%44.2% 60.1% 66.4% 70.2% Metformin HCl 0.0% 25.1% 39.4% 70.9% 88.8% 97.2%18 Pioglitazone HCl 0.0% 0.5% 0.7% 1.0% 1.2% 1.4% Metformin HCl 0.0%25.1% 39.4% 70.9% 88.8% 97.2% 19 Sitagliptin phosphate 0.0% 15.0% 23.8%26.9% 29.5% 34.2% monohydrate Metformin HCl 0.0% 25.1% 39.4% 70.9% 88.8%97.2% 20 Voglibose 0.0% 42.3% 58.9% 85.7% 93.4% 99.8% Metformin HCl 0.0%25.1% 39.4% 70.9% 88.8% 97.2% 21 Voglibose 0.0% 30.3% 44.9% 77.6% 90.9%99.1% 22 Glimepiride 0.0% 44.2% 60.1% 66.4% 70.2% Voglibose 0.0% 30.3%44.9% 77.6% 90.9% 99.1% 23 Pioglitazone HCl 0.0% 0.5% 0.7% 1.0% 1.2%1.4% Voglibose 0.0% 30.3% 44.9% 77.6% 90.9% 99.1% 24 Levosulpiride 0.0%32.1% 42.6% 68.9% 92.7% 98.7% 25 Mosapride citrate 0.0% 33.2% 45.1%70.6% 88.9% 99.0% 26 Trimebutine 0.0% 30.6% 40.8% 66.7% 85.8% 98.8% 27Itopride HCl 0.0% 34.8% 46.7% 72.5% 90.3% 99.9% 28 Cilostazol 0.0% 43.2%48.6% 54.6% 64.7% 75.7% 29 Limaprost 0.0% 27.6% 30.6% 37.2% 48.5% 60.6%Alpha-Cyclodextrin Clathrate 30 Sarpogrelate HCl 0.0% 30.2% 35.4% 45.2%59.7% 75.0% 31 Nifedipine 0.0% 3.3% 6.8% 20.5% 37.8% 59.7% 32 LosartanPotassium 0.0% 99.3% Nifedipine 0.0% 3.3% 6.8% 20.5% 37.8% 59.7% 33Valsartan 0.0% 50.1% 69.9% 85.6% 93.7% 99.2% Nifedipine 0.0% 3.3% 6.8%20.5% 37.8% 59.7% 34 Telmisartan 0.0% 43.6% 62.4% 76.8% 87.1% 97.5%Nifedipine 0.0% 3.3% 6.8% 20.5% 37.8% 59.7% 35 Olmesartan medoxomil 0.0%98.1% Nifedipine 0.0% 3.3% 6.8% 20.5% 37.8% 59.7% 36 Candesartancilexetil 0.0% 0.0% 0.2% 0.4% Nifedipine 0.0% 3.3% 6.8% 20.5% 37.8%59.7% 37 Benidipine HCl 0.0% 4.5% 7.6% 25.2% 45.1% 70.9% 38 LosartanPotassium 0.0% 99.3% Benidipine HCl 0.0% 4.5% 7.6% 25.2% 45.1% 70.9% 39Valsartan 0.0% 50.1% 69.9% 85.6% 93.7% 99.2% Benidipine HCl 0.0% 4.5%7.6% 25.2% 45.1% 70.9% 40 Telmisartan 0.0% 43.6% 62.4% 76.8% 87.1% 97.5%Benidipine HCl 0.0% 4.5% 7.6% 25.2% 45.1% 70.9%

TABLE 8 Dissolution rate at pH 6.8 under conditions of second method 50rpm over time (%) Example Ingredient 0 min 30 min 60 min 180 min 360 min600 min 41 Olmesartan medoxomil 0.0% 98.1% Benidipine HCl 0.0% 4.5% 7.6%25.2% 45.1% 70.9% 42 Candesartan cilexetil 0.0% 0.0% 0.2% 0.4%Benidipine HCl 0.0% 4.5% 7.6% 25.2% 45.1% 70.9% 43 Carvedilol 0.0% 5.7%8.4% 27.1% 48.6% 73.8% 44 Losartan Potassium 0.0% 99.3% Carvedilol 0.0%5.7% 8.4% 27.1% 48.6% 73.8% 45 Valsartan 0.0% 50.1% 69.9% 85.6% 93.7%99.2% Carvedilol 0.0% 5.7% 8.4% 27.1% 48.6% 73.8% 46 Telmisartan 0.0%43.6% 62.4% 76.8% 87.1% 97.5% Carvedilol 0.0% 5.7% 8.4% 27.1% 48.6%73.8% 47 Olmesartan medoxomil 0.0% 98.1% Carvedilol 0.0% 5.7% 8.4% 27.1%48.6% 73.8% 48 Candesartan cilexetil 0.0% 0.0% 0.2% 0.4% Carvedilol 0.0%5.7% 8.4% 27.1% 48.6% 73.8% 49 Atenolol 0.0% 8.2% 13.4% 30.5% 46.3%60.1% 50 Losartan Potassium 0.0% 99.3% Atenolol 0.0% 8.2% 13.4% 30.5%46.3% 60.1% 51 Valsartan 0.0% 50.1% 69.9% 85.6% 93.7% 99.2% Atenolol0.0% 8.2% 13.4% 30.5% 46.3% 60.1% 52 Telmisartan 0.0% 43.6% 62.4% 76.8%87.1% 97.5% Atenolol 0.0% 8.2% 13.4% 30.5% 46.3% 60.1% 53 Olmesartanmedoxomil 0.0% 98.7% Atenolol 0.0% 8.2% 13.4% 30.5% 46.3% 60.1% 54Candesartan cilexetil 0.0% 0.0% 0.2% 0.4% Atenolol 0.0% 8.2% 13.4% 30.5%46.3% 60.1% 55 Valaciclovir HCl 0.0% 35.1% 39.4% 50.0% 63.2% 72.7% 56Choline Alfoscerate 0.0% 25.0% 41.7% 71.5% 88.3% 98.4% 57Acetyl-l-carnitine HCl 0.0% 31.3% 46.8% 70.1% 87.9% 98.0% 58 VenlafaxineHCl 0.0% 52.4% 57.8% 63.9% 74.1% 85.6% 59 Risperidone 0.0% 52.0% 53.0%58.6% 67.9% 78.8% 60 Quetiapine 0.0% 51.9% 58.3% 64.7% 76.9% 88.4% 61Gabapentin 0.0% 34.8% 36.2% 50.6% 63.4% 72.8% 62 Pregabalin 0.0% 52.6%55.7% 60.2% 70.5% 81.3% 63 Levetiracetam 0.0% 51.5% 59.1% 66.0% 78.1%90.2% 64 Rivastigmine 0.0% 52.1% 55.2% 60.6% 68.9% 81.0% 65 Aceclofenac0.0% 51.3% 58.0% 63.9% 74.1% 87.7% 66 Eperisone HCl 0.0% 36.1% 38.6%52.6% 66.1% 76.4% 67 Bepotastine besilate 0.0% 52.6% 55.1% 59.8% 68.7%79.8% 68 Rosuvastatin calcium 0.0% 99.9% Metformin HCl 0.0% 25.1% 39.4%70.9% 88.8% 97.2% 69 Acetaminophen 0.0% 51.7% 60.4% 78.1% 91.8% 98.0%Tramadol HCl 0.0% 27.1% 41.9% 71.1% 88.9% 96.3%

1. A pharmaceutical composition comprising a sustained-release partcoated with a water-insoluble polymer on the surface, comprising a firstactive pharmaceutical ingredient, at least one release control baseselected from the group consisting of water-insoluble polymer, andwater-soluble viscous polymer, and a pharmaceutically acceptablecarrier; and an immediate release part comprising a second activepharmaceutical ingredient and a pharmaceutically acceptable carrier. 2.The pharmaceutical composition of claim 1, wherein the water-insolublepolymer exhibits solubility of 0.0001 g/ml or less in an aqueous solventat any pH.
 3. The pharmaceutical composition of claim 1, wherein thewater-soluble viscous polymer exhibits solubility of 0.01 g/ml or morein an aqueous solvent at any pH, and absorbs an aqueous solvent in anaqueous solution of 10% w/v, 20° C. to exhibit viscosity change of 1mPas or more, based on the dry state.
 4. The pharmaceutical compositionof claim 1, wherein the sustained-release part is additionally coatedwith a water-soluble viscous polymer.
 5. The pharmaceutical compositionof claim 1, wherein the sustained-release part and the immediate-releasepart are in the form of independent granules, and the granules aremixed.
 6. The pharmaceutical composition of claim 1, wherein the firstactive pharmaceutical ingredient, the release control base, and thepharmaceutically acceptable carrier are mixed.
 7. The pharmaceuticalcomposition of claim 1, wherein the first active pharmaceuticalingredient in the sustained-release part is a single or complexingredient.
 8. The pharmaceutical composition of claim 1, wherein thesecond active pharmaceutical ingredient in the immediate-release part isa single or complex ingredient.
 9. The pharmaceutical composition ofclaim 7, wherein the first active pharmaceutical ingredient is one ormore selected from the group consisting of acetaminophen, tramadol,Niacin, Pitavastatin, Rosuvastatin, Atorvastatin, Rebamipide, Metformin,Glimepiride, Pioglitazone, Sitagliptin, Voglibose, Levosulpiride,Mosapride, Trimebutine, Itopride, Cilostazol, Limaprost, Sarpogrelate,Nifedipine, Losartan, Valsartan, Telmisartan, Olmesartan, Candesartan,Benidipine, Carvedilol, Atenolol, Valaciclovir, Choline Alfoscerate,Acetyl-l-carnitine, Venlafaxine, Risperidone, Quetiapine, Gabapentin,Pregabalin, Levetiracetam, Rivastigmine, Aceclofenac, Eperisone,Bepotastine, Acyclovir, and a pharmaceutically acceptable salt thereof.10. The pharmaceutical composition of claim 8, wherein the second activepharmaceutical ingredient is one or more selected from the groupconsisting of acetaminophen, tramadol, Niacin, Pitavastatin,Rosuvastatin, Atorvastatin, Rebamipide, Metformin, Glimepiride,Pioglitazone, Sitagliptin, Voglibose, Levosulpiride, Mosapride,Trimebutine, Itopride, Cilostazol, Limaprost, Sarpogrelate, Nifedipine,Losartan, Valsartan, Telmisartan, Olmesartan, Candesartan, Benidipine,Carvedilol, Atenolol, Valaciclovir, Choline Alfoscerate,Acetyl-l-carnitine, Venlafaxine, Risperidone, Quetiapine, Gabapentin,Pregabalin, Levetiracetam, Rivastigmine, Aceclofenac, Eperisone,Bepotastine, Acyclovir, and a pharmaceutically acceptable salt thereof.11. The pharmaceutical composition of claim 2, wherein thewater-insoluble polymer is one or more selected from the groupconsisting of water-insoluble cellulose, water-insoluble cellulosederivatives, polymethacrylate, polyalkylacrylate,methacrylate-ethylacrylate based copolymer, and a combination thereof.12. The pharmaceutical composition of claim 3, wherein the water-solubleviscous polymer is one or more selected from the group consisting ofhydroxylalkylcellulose, hydroxypropylalkylcellulose, polyalkyleneoxide,sodium alginate, povidone, natural or synthetic gums, polyvinylalcohol,carboxymethylcellulose sodium, and a combination thereof.
 13. Thepharmaceutical composition of claim 1, wherein the pharmaceuticalcomposition is in the form of a tablet.